T helper responses in early life in the mouse and, notably, allergen-specific responses in human infants are biased to Th2 function. This early life Th2 dominance is associated with the development of Th2- mediated diseases, such as allergy and asthma. With Th2-mediated diseases on the rise, there is a clear need for the development of new approaches to prevent and treat pathological Th2 activity. However, what is currently lacking is a thorough understanding of the basis of early life Th2 function. This information is critical for formulating effective strategies to target Th2-mediated pediatric disease. To this end, the long term goals of this proposal are to determine the molecular and cellular regulation of neonatal Th2 responses. Specific Aim 1will focus on the molecular events governing neonatal Th2 function. We have generated compelling evidence that the neonatal Th2 bias is regulated, at least in part, at the epigenetic level. Naive neonatal CD4+ cells, unlike adult CD4+cells, show demethylation of a key regulatory region in the Th2 locus. Thus, we will further investigate this phenomenon, its specificity and its developmental origin, and test the idea that DMAmethylation is critical for defining developmental differences in Th2 effector differentiation and function. Specific Aims 2 and 3 will examine cellular components enriched in neonates that are strong candidates for being the major sources of Th2 activity. First, since many neonatal CD4+ cells are likely to be direct descendants of fetal precursors, Specific Aim 2 will test the idea that neonatal Th2 cells are of fetal origin. Support for this hypothesis comes from our observation that peripheral CD4+ cells derived from fetal thymocytes have enhanced Th2 function. Second, the peripheral CD4+ population in neonates contains proportionally many more recent thymic emigrants (RTE) than found in peripheral populations in adults. Therefore, Specific Aim 3 will address the hypothesisthat RTE are the source of Th2 function in neonates. This idea is supported by our findings that the function of peripheral CD4+ cells in neonates resembles that of RTE in adults.